The overall objectives of this UO1 are to provide support for both Phase I trials of new anti-cancer agents and for pharmacokinetic, pharmacodynamic and other laboratory correlative studies in cancer patients receiving these agents. These studies will be performed by the Harvard Phase I Oncology Group. The specific goals are the following: l) to define the toxicities of new anti-cancer agents inpatients with advanced cancer; 2) to define the pharmacokinetic characteristics (absorption, distribution, metabolism and elimination) and pharmacodynamics (effects at the biochemical and molecular levels) of these agents; and 3) to determine a treatment regimen suitable for evaluation of anti-tumor activity in Phase II trials. The scope of the program will include Phase I and laboratory studies of: 1) investigational new cytotoxic drugs; 2) differentiating agents; and 3) anti-angiogenesis agents. In addition to pharmacokinetic analyses, laboratory studies depending on the agent, will focus on regulation of specific gene expression, changes in signal transduction pathways, induction of differentiation and inhibition of angiogenesis. Since the agents to be studied are unknown at this point, we have selected as examples the following: l) bryostatin l, an activator of protein kinase C and inducer of differentiation; and 2) TNP-470, a new inhibitor of angiogenesis. Bryostatin l was first shown by us to be an effective inducer of human myeloid leukemia cell differentiation. Moreover, development of TNP-470 as a therapeutic agent was the result of fundamental work on angiogenesis in our laboratories. Phase I pharmacokinetic trials of bryostatin l and TNP-470, as well as the appropriate laboratory correlates of pharmacodynamic or biologic response, are included as examples of investigator-originated research to be conducted by our group. The specific aims are l) to conduct a Phase I, pharmacokinetic and pharmacodynamic trial of bryostatin l in combination with all-trans retinoic acid; and 2) to conduct a Phase I pharmacokinetic and pharmacodynamic trial of the angiogenesis inhibitor TNP-470.